Extracellular adenosine acts as a local modulator at four subtypes of adenosine receptors, namely, A1, A2A, A2B, and A3, which are involved in numerous physiological and pathophysiological processes. Fredholm et al., Pharmacol. Rev. 2001; 53:527-52. For example, adenosine attenuates the effects of ischemia in the heart and brain. Acting through the A2A adenosine receptor, it suppresses prolonged inflammation; Ohta et al., Nature 2001; 414:916-920; and causes vasodilation and inhibits platelet aggregation, thus increasing the amount of oxygen available to an organ under stress. Adenosine agonists selective for the A3 adenosine receptor are of interest as cerebroprotective, cardioprotective, and anticancer agents. von Lubitz et al., Eur. J. Pharmacol., 1994, 263:59-67; Liu et al., Cardiovasc Res., 1994, 28:1057-61; Strickler et al., J. Clin. Invest., 1996, 98:1773-9; Fishman et al., Oncogene, 2004, 23:2465-71.
The potential utility of A1 and A2-selective agents in therapeutic applications has been limited by accompanying side effects, given the ubiquitous nature of the A1 and A2 receptors. The distribution of the A3 adenosine receptor, by contrast, is fairly limited, being found primarily in the CNS, brain, testes, and immune system, where it appears to be involved in the modulation of release from mast cells of mediators of the immediate hypersensitivity reaction (Ramkumar et al., J. Biol. Chem., 268, 16887-16890 (1993)). The limited distribution of the A3 adenosine receptor provides a basis for predicting that A3-selective compounds may be more useful than A1- and A2-selective compounds as potential therapeutic agents.
Accordingly, there is a great interest for finding A3 adenosine receptor agonists, as shown by the patenting activity in this area; see, for example, U.S. Pat. Nos. 5,773,423 and 5,688,774; and U.S. Published Patent Application No. 2003/0216412 A1. Therefore, there is a desire for A3 adenosine receptor agonists, especially those that are selective to A3 adenosine receptor over the A1 and A2 adenosine receptors.
Attempts have been made to covalently link certain drugs, for example, taxol, cisplatin, methotrexate, and ibuprofen, to dendrimers, which are polymers made from branched monomers through the iterative organic synthesis by adding one layer (i.e., generation) at each step to provide a symmetrical structure. Such dendrimer conjugates have one or more advantages, for example, altered pharmacokinetics, decreased toxicity, and increased solubility. Agonists and antagonists of the receptors of the G-protein coupled receptor (GPCR) superfamily are useful in the treatment of a number of diseases, for example, the agonist of one member of the GPCR superfamily, the A3 adenosine receptor, is useful for treating a number of diseases as set forth in the above patents and published application. There is a desire to obtain dendrimer conjugates of agonists and antagonists of the GPCR superfamily of receptors.